Carboxylate Assisted Ni-Catalyzed C-H Bond Allylation of Benzamides

Article abstract of DOI:10.1002/chem.201500639

A one-step synthetic method was developed for allylation of benzamides using Ni(COD)₂/RCO₂H and [Ni(μ-H₂O)(OOCCMe₃)₂(HOOCCMe₃)₂]₂ (A′) catalytic system. Efficient, well-defined, air and moisture-stable Ni-pivalate complex was isolated and employed in catalytic allylation. The influence of solvent on product selectivity was also investigated. Nickel-back: A one-step synthetic method was developed for the allylation of benzamides using in situ formed nickel carboxylate Ni(COD)₂/RCO₂H catalyst (see scheme). The air and moisture stable Ni-pivalate complex was isolated and employed in catalytic allylation. The influence of solvent on product selectivity is discussed.

Full text of DOI:10.1002/chem.201500639

DOI: 10.1002/chem.201500639
Communication
&
Synthetic Methods
Carboxylate Assisted Ni-Catalyzed CÀH Bond Allylation of
Benzamides
Nagaraju Barsu, Deepti Kalsi, and Basker Sundararaju*[a]
tani et al. showed in the course of alkylation of arene with NiII/
Abstract: A one-step synthetic method was developed for
allylation of benzamides using Ni(COD)2/RCO2H and [Ni(m-
H2O)(OOCCMe3)2(HOOCCMe3)2]2 (A’) catalytic system. Effi-
cient, well-defined, air and moisture-stable Ni–pivalate
complex was isolated and employed in catalytic allylation.
The influence of solvent on product selectivity was also in-
vestigated.
PPh3 catalysts, only one example of allylation with allyl bromi-
de.[7a] In this line, we report now a novel synthetic method for
allylation of arenes using nickel-carboxylate[11] catalyst without
significant isomerization. Allylation of benzamides with 8-ami-
noquinoline (NHQ) as a bidentate auxiliary directing group in
the presence of Ni(COD)2 as a catalyst precursor along with
carboxylic acid, progress remarkably.
To find out functional group tolerances and their regioselec-
tivity using nickel as a catalyst various nickel precursors were
screened (Table 1). Among all Ni(COD)2 (10 mol%) in combina-
tion with m-toluic acid as a co-catalyst (20 mol%) with amide
1a (0.1 mmol), allyl bromide 2 (0.3 mmol) and Na2CO3 in DMF
at 1408C (oil-bath temperature) for 18 h gave complete con-
version with 89% isolated yield of o-allylated amide 3a along
with isomerized product 4a in 11:1 ratio (Table 1, entry 6).[12]
Further screening of the solvent revealed that complete con-
version was achieved with DMA and o-xylene (Table 1, entry 9
and 10), whereas toluene gave only 15% conversion (entry 1,
Table S2 in the Supporting Information). Replacement of m-
toluic acid by a sterically hindered acid such as pivalic acid,
1,3,5-trimethylbenzoic acid and adamantyl carboxylic acid gave
complete conversion with a similar 3a/4a ratio. The allylation
reaction was unsuccessful upon changing the allylic substrate
from bromide to chloride or carbonate or alcohol. Switching
the base from Na2CO3 to KHCO3 did not alter the outcome of
the allylation reaction and complete conversion was also ob-
served. Further optimization revealed that the reaction goes
for completion in 6 h (entry 11, Table 1). While our studies were
ongoing, allylation reaction of functional arene using allyl
phosphate as a coupling partner with Ni(COD)2/PCy3 catalytic
system was reported.[7g] The reaction performed under our re-
action condition using allyl phosphate did not give us the ex-
pected product 3a. This clearly emphasizes that the synthetic
method (or the catalyst) developed by us is distinctly different
from the recent report with better yield and product selectivi-
ty.[7g]
Functionalization of CÀH bonds is an active area of research
which became more intense after the discovery of catalytic CÀ
H bond functionalization using precious metal catalyst[1,2] de-
veloped by Murai et al. However, the recent focus on develop-
ing synthetic methodology for various functionalizations using
inexpensive and more abundant metal catalysts is a challenging
task.[3] In particular nickel catalysts attract interest as Ni0 spe-
cies offer facile oxidative addition and nickel complexes pro-
vide accessible variable oxidation states which are key require-
ments for effective catalysts, successfully employed in numer-
ous novel transformations.[4] Importance of bidentate chelate
assisted activation/functionalization of CÀH bond was intro-
duced by Daugulis and co-worker.[5] Contributions for further
development of this approach using nickel catalyst by Chatani
et al. and others appear very promising.[6,7] Although emerging
results with these catalysts are encouraging, the use of nickel
catalysts for chemical transformation is quite rare, likely due to
the lack of understanding of the mechanism and reaction
pathway as compared to precious metal catalysts. Owing to
the advantage of the allyl group for various useful synthetic
modifications in functionalization of the C=C bond and alkene
metathesis, assessment of an efficient approach to introduce
an allyl moiety without isomerization has attracted much at-
tention for numerous regio- and stereoselective transforma-
tions.[8] In addition, allyl arenes are found to be in various natu-
ral products and biologically active compounds.[9] The existing
methodology available for allylation of arene requires reactive
organometallic reagent for cross coupling, which suffers from
functional group tolerance. Chelate-assisted CÀH bond allyla-
tion is known with Rh and Fe metal complexes, however re-
ports based on nickel catalysts are rare in the literature.[10] Cha-
In order to enlarge the scope of the developed synthetic
method, various substituted arenes were investigated in detail
(Table 2). Good yields were obtained while employing electron-
donating substituent on the arene ring 3b–c (74–87%) com-
pared with electron-withdrawing substituent 3d–g (36–53%).
Further, we noticed that allylation occurs on a less hindered
site of arene when meta-substituted benzamides were em-
ployed which is likely due to steric influence of 3b–c, 3 f. Ally-
lation reaction works remarkably with heteroaromatic amide in
moderate yield of 3h (46%).
[a] N. Barsu, D. Kalsi, Prof. B. Sundararaju
Department of Chemistry
Indian Institute of Technology Kanpur, Kanpur (India)
E-mail: basker@iitk.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500639.
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Table 1. Optimization of allylation of benzamide with allyl bromide.[a]
Table 3. [Ni]-catalysed bis allylation of benzamide.
Entry[a]
[Ni]
R-CO2H
T [8C]
3a/4a[b]
Yield [%][c]
1
2
3
4
5
6
7
8
Ni(acac)2
Ni(OAc)2
NiCl2·6H2O
Ni(OTf)2
m-toluic acid
m-toluic acid
m-toluic acid
m-toluic acid
m-toluic acid
m-toluic acid
Mes-CO2H
pivalic acid
m-toluic acid
m-toluic acid
m-toluic acid
PCy3
140
140
140
140
140
140
140
140
140
140
140
140
140
–
n.r.[d]
53
66
68
85
89
1.3:1
1.1:1
3:1
10:1
11:1
11:1
10:1
6:1
Ni(OH)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(OTf)2
>99[e]
>99[e]
>99[e,f]
>99[e,g]
>99[h]
89[e]
9
10
11
12
13
2:1
11:1
13:1
12:1
PPh3
72[e]
[a] All reactions were carried out in nitrogen atmosphere using 1a/2/[Ni]/
acid/base in 0.2/0.6/0.02/0.04/0.4 mmol in 1 mL DMF at 1408C (oil-bath
temperature) for 18 h. [b] Ratio was determined by 1H NMR spectroscopy
from crude mixture. [c] Isolated yield of amide 3a. [d] No reaction.
[e] Conversion instead of yield, calculated using gas chromatogram in the
presence of dodecane as an internal standard. [f] Dimethyl acetamide
used as a solvent. [g] o-Xylene used as a solvent. [h] Reaction was carried
out in 6 h.
[a] All reactions were carried out in nitrogen atmosphere using 1a/2/
Ni(COD)2/3-methylbenzoicacid/base in 0.2/1.0/0.02/0.04/0.4 mmol in 1 mL
solvent at 1408C (oil-bath temperature) for 22 h; [b] 20 mol% of 2,4,6-tri-
methyl benzoic acid used.
Next we further extended the reaction scope with other al-
lylic substrates. Undeniably the reaction worked well when
other allylic substrates were employed, in moderate
to good yield. All reactions were regioselective and
linear isomers were obtained in a mixture of stereo-
isomers 3i–l. Addition of ÀCH2 group in 1i between
benzene and carbonyl group of amide did not give
any conversion reflecting the necessity of the alpha-
substituent next to the carbonyl group. Homocou-
pling reaction is preferred over the desired allylation
when the reaction is performed with cinnamyl bro-
mide and 1a under the optimized reaction condi-
tions. Changing the reaction parameters such as tem-
perature, time or solvent did not give us the desired
results with our catalytic system.
Table 2. Optimization of allylation of benzamide with allyl bromide.
Selective bis-allylation of CÀH bonds of benzamide
is difficult to perform under normal circumstances, as
it often tends to give a mixture of mono- and bis-al-
lylated amide. Selective bis-allylated amide is of inter-
est for acyclic diene metathesis (ADMET) polymeri-
zation. Our investigation revealed that bis-allylation
could be possible by switching solvent from DMF to
NMP (N-methylpyrrolidine) with various benzamide
and allyl bromides at 1408C for 18 h. Bis-allylated
electron-rich aromatic amides were obtained as
major compounds in good yield (61–90%; Table 3).
Electron-poor aromatics gave complete conversion
but resulted in a mixture of mono- and bis-allylated
product.
The developed synthetic methodology for mono-
allylation was tested for bulk-scale production and it
worked excellently with an expected allylated prod-
uct in 70% yield (Scheme 1). Several control experi-
[a] All reactions were carried out in Nitrogen atmosphere using 1a/2/[Ni]/3-methyl-
benzoic acid/base in 0.2/0.6/0.02/0.04/0.4 mmol in 1 mL solvent at 1408C (oil-bath
temperature) for 18 h; [b] 20 mol% of 2,4,6-trimethyl benzoic acid used. [c] In paren-
thesis ratio of 3:4.
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Scheme 1. Gram-scale synthesis of CÀH allylated benzamide.
ments were conducted to understand the reaction pathways
and mechanism.
Competitive experiments performed with electron-rich and
electron-poor amide using allyl bromide under our reaction
conditions show that allylation is favoured with electron-rich
substrates (Scheme 2a). The reaction performed in the pres-
ence of excess 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO;
3 equiv) did not affect the product formation, which may pos-
sibly explain the non-radical reaction pathway involved in the
catalytic cycle (Scheme 2b).
We next, turned our attention to the isolation of the in situ
formed nickel-carboxylate complex either from nickel(0) or
nickel(II) precursors. Numerous attempts made to isolate the in
situ formed nickel-carboxylate complex from Ni(COD)2 were
not successful. The reaction conditions utilized in optimization
enforced us to try nickel(II) precursor. Nickel hydroxide with
pivalic acid (excess) in toluene at reflux conditions in 3 h
guided us to stabilize the air and moisture-stable [Ni(m-
H2O)(OOCCMe3)2(HOOCCMe3)2]2 dimer complex A’, which is in
accord with the reported literature.[13] The isolated complex
was further tested for catalytic allylation of 1a with allyl bro-
mide and gave the expected product in 74% yield without any
isomerization in 5 h as compared with the reported Ni(OTf)2/
Scheme 2. Control experiments.
with RCO2H of NiÀN bond to give 3 with the regeneration of
catalyst.
In summary, we have reported a novel carboxylate-assisted
allylation of various benzamides using nickel(II) catalyst, easily
made on addition of RCO2H to Ni(COD)2 and a preformed
[Ni(m-H2O)(OOCCMe3)2(HOOCCMe3)2]2 (A’) catalyst. The devel-
oped phosphine-free synthetic methodology is much more
convenient than the existing synthetic methods.[7a,g] Moreover,
the reported reaction conditions are suitable for various substi-
tuted arenes. Air and moisture-stable nickel–pivalate complex
was isolated and the activity was examined in allylation reac-
tions. Also, we have shown the influence of solvent on achiev-
ing bis-allylated product, which is extremely rare in the litera-
ture. To fine-tune the catalytic activity and understand the role
[7a,h]
[7g]
PPh3
or Ni(COD)2/PCy3
catalytic systems requiring 24–
30 h, respectively (Scheme 3). The isolated nickel pivalate cata-
lyst A’ was efficient when we employed with other substrate
with shorter reaction time compared with the in situ nickel cat-
alyst. Final conclusions cannot be drawn at this stage
regarding whether the in situ formed complex is
monomeric or dimeric in nature. Further stoichiomet-
ric reactions are currently underway to find the active
species.
Based on the above observation, a proposed
mechanism for the CÀH allylation of amide is given
in Scheme 4. This was based on the high catalytic ac-
tivity observed both with Ni0 and NiII precatalysts
during our screening (Table 1). The formation of the
active catalytic species Ni(OCOR)2 (A) was proposed
to form either from Ni0 (Path I)[13b] or NiII species
(Path II).
Amide 1a is expected to coordinate with complex
A through N,N coordination to generate B, which
upon base-assisted deprotonation of CÀH bond pro-
vides reversible cyclometallated complex C. High
valent cationic p-allyl nickel(IV) complex D is expect-
ed to be formed from intermediate C with allyl bro-
mide through oxidative addition.[7a,h] Complex D un-
dergoes subsequent reductive elimination leading to
intermediate E or E’ which then undergo protonation Scheme 3. CÀH allylation of amide with isolated Ni–pivalate complex A’.
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Keywords: allylation · catalysts · CÀH bond activation · nickel ·
synthetic methods
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Received: February 14, 2015
Published online on May 26, 2015
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